miR-206 knockout shows it is critical for myogenesis and directly regulates newly identified target mRNAs.
The muscle specific miRNA, miR-206, is important for the process of myogenesis; however, studying the function of miR-206 in muscle development and differentiation still proves challenging because the complement of mRNA targets it regulates remains undefined. In addition, miR-206 shares close sequence similarity to miR-1, another muscle specific miRNA, making it hard to study the impact of miR-206 alone in cell culture models. Here we used CRISPR/Cas9 technology to knockout miR-206 in C2C12 muscle cells. We show that knocking out miR-206 significantly impairs and delays differentiation and myotube formation, revealing that miR-206 alone is important for myogenesis. In addition, we use an experimental affinity purification technique to identify new mRNA targets of miR-206 in C2C12 cells. We identified over one hundred mRNAs as putative miR-206 targets. Functional experiments on six of these targets indicate that Adam19, Bgn, Cbx5, Smarce1, and Spg20 are direct miR-206 targets in C2C12 cells. Our data show a unique and important role for miR-206 in myogenesis.


A systematic review of influences on implementation of peer support work for adults with mental health problems.
The evidence base for peer support work in mental health is established, yet implementation remains a challenge. The aim of this systematic review was to identify influences which facilitate or are barriers to implementation of mental health peer support work. Data sources comprised online databases (n = 11), journal table of contents (n = 2), conference proceedings (n = 18), peer support websites (n = 2), expert consultation (n = 38) and forward and backward citation tracking. Publications were included if they reported on implementation facilitators or barriers for formal face-to-face peer support work with adults with a mental health problem, and were available in English, French, German, Hebrew, Luganda, Spanish or Swahili. Data were analysed using narrative synthesis. A six-site international survey [Germany (2 sites), India, Israel, Tanzania, Uganda] using a measure based on the strongest influences was conducted. The review protocol was pre-registered (Prospero: CRD42018094838). The search strategy identified 5813 publications, of which 53 were included. Fourteen implementation influences were identified, notably organisational culture (reported by 53% of papers), training (42%) and role definition (40%). Ratings on a measure using these influences demonstrated preliminary evidence for the convergent and discriminant validity of the identified influences. The identified influences provide a guide to implementation of peer support. For services developing a peer support service, organisational culture including role support (training, role clarity, resourcing and access to a peer network) and staff attitudes need to be considered. The identified influences provide a theory base to prepare research sites for implementing peer support worker interventions.


RAS gene mutations in multiple myeloma and related monoclonal gammopathies.
The presence of RAS gene mutations in precancerous lesions suggests that they participate in the early stages of neoplastic development. Furthermore, neoplastic progression from monoclonal gammopathy of undetermined significance (MGUS) to overt multiple myeloma (MM) have been frequently observed. These observations prompted us to study the pathogenetic role of RAS genes in MM and related monoclonal gammopathies. DNA from 18 patients with monoclonal gamma-globulinemia including 12 MM were investigated for the presence of N- and K-RAS gene mutations by polymerase chain reaction (PCR)/oligonucleotide hybridization. Mutations involving codons 12, 13 or 61 of N-RAS gene were identified in 3 of the 12 MM patients, 1 of the solitary plasmacytoma patients and none of the 3 of the MGUS patients. In the case of plasmacytoma, RAS mutations were detected in his bone marrow specimens.


[Importance of microbiologic examination of vaginal secretions in the reproductive period].
Vaginal infections, during reproductive period are frequent and although not life treating, they can affect their normal functions. They can also affect women's fertility as well as the course of pregnancy. The outcome of pregnancy can be endangered due to the possibility of infection of newborn while passing trough birth canal of the infected mother. As statistically shown, bacterial vaginosis is considerably more often found with the patients having precancerous changes on cervix, or diagnosed cancer of cervix, comparing with women with healthy cervix. It can also cause the appearance of postoperative pelvic cellulitis after hysterectomy. On the other side, the presence of S. agalactiae in vaginal secretion may cause very serious and lethal infections of the newborn such as meningitis, pneumonia and sepsis. As for protozoa T. vaginalis it has been shown that it could cause reduced fertility ability and that during pregnancy it could damage fetal membranes and bring to its premature rupture and premature birth. There is also increased risk of cervix cancer. During reproductive period of women especially if risk factors are existing such as hormone therapy, diabetes mellitus type 1 and applications of wide range antibiotics, vaginal fungal infections caused by Candida can frequently appear. These infection apart from the discomfort like itch and affluent secretion they can also mean diagnostic and therapeutical problem. Regular microbiological test of women are highly recommended during reproductive period as standard for bacterial vaginosis, fungal and trichomonas infections. If those results appear negative, further microbiological tests are necessary. Such tests which are more elaborate, more timely and more expensive are referring to tests on chlamydia, microplasma and some viruses that can also be the cause of vaginal secretion disbalance in women during reproductive period.


Efficacy of selamectin administered topically to pregnant and lactating female dogs in the treatment and prevention of adult roundworm (Toxocara canis) infections and flea (Ctenocephalides felis felis) infestations in the dams and their pups.
The efficacy of selamectin in the treatment and prevention of naturally acquired Toxocara canis infections and experimentally induced flea (Ctenocephalides felis felis) infestations in dams and their suckling pups was evaluated by administering selamectin to the adult females only, approximately 40 and 10 days before parturition and 10 and 40 days after parturition. Unit doses of the commercial formulation of selamectin were administered to the dams to provide at least the minimum recommended dosage of 6mgkg(-1) (range, 6-12mgkg(-1)). Dams and their pups were housed in carpeted environments able to support the flea life cycle. Flea infestations were established initially by experimental infestation before treatment administration and by repeated re-infestation of dams at approximately weekly intervals throughout the study, which was completed 45 days after parturition. There were no adverse drug experiences related to treatment with selamectin and no treatment-related mortalities. Percentage reductions in geometric mean T. canis faecal egg counts for the selamectin-treated dams, compared with those receiving the negative-control treatment (vehicle only) were 99.7% at the end of the study (P=0.0001). Geometric mean faecal egg counts in pups from selamectin-treated females were reduced by > or =96% on the 24th and 34th days after birth (P=0.0001), and the number of adult worms recovered from the gastrointestinal tract of pups from selamectin-treated dams was reduced by 98.2% (P=0.0001), compared with that for pups from dams treated with the vehicle only. Percentage reductions in geometric mean flea counts for selamectin-treated dams and their pups, compared with vehicle-treated dams and their pups, were > or =99.8% (P=0.0001) and 100% (P=0.0001), respectively, throughout the study. Thus, selamectin administered topically at a minimum unit dosage of 6mgkg(-1) to dams with naturally acquired T. canis infections and experimentally induced C. felis infestations was safe and highly effective in the treatment, control, and prevention of adult T. canis infection and C. felis infestation affecting both the dams and their pups.


The role of the spleen in experimental pneumococcal bacteremia.
The importance of the spleen in host defense against pneumococcal bacteremia has been suggested by a number of experimental models as well as the occurrence of the syndrome of overwhelming pneumococcal sepsis in asplenic individuals. We studied the mechanism of splenic protection against pneumococcal bacteremia using a guinea pig model. Rates of removal of pneumococci from the blood stream in normal and splenectomized guinea pigs were compared with the extent of hepatic and splenic sequestration of radiolabeled organisms for three different types of pneumococci. A relationship was found between the virulence of a pneumococcus for normal guinea pigs, the extent to which it is cleared by the spleen, and the magnitude of the defect in blood stream sterilization induced by splenectomy. The spleen plays an increasingly important role in the clearance of progressively more virulent organisms, for which hepatic clearance cannot compensate. Thus, the division between hepatic and splenic clearance of bacteremia is a key determinant of the outcome of experimental pneumococcal infection.


[Patients with adquired mouth, nose and ear affections: basic needs altered and expectations concerning nursing care].
The study identifies the most basic human needs commonly altered on patients with adquired mouth, nose and ear affections, their expectations concerning nursing procedures and the relation of those expectations to the expressixe and instrumental roles of the nurse.


High Molecular Diversity of Organic Nitrogen in Urban Snow in North China.
Snow serves as a vital scavenging mechanism to gas-phase and particle-phase organic nitrogen substances in the atmosphere, providing a significant link between land-atmosphere flux of nitrogen in the surface-earth system. Here, we used optical instruments (UV-vis and excitation-emission matrix fluorescence) and a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS) to elucidate the molecular composition and potential precursors of snow samples collected simultaneously at four megacities in North China. The elemental O/N ratio (≥3), together with the preference in the negative ionization mode, indicates that the one and two nitrogen atom-containing organics (CHON1 and CHON2) in snow were largely in the oxidized form (as organic nitrates, -ONO2). This study assumed that scavenging of particle-phase and gas-phase organic nitrates might be significant sources of CHON in precipitation. A gas-phase oxidation process and a particle-phase hydrolysis process, at a molecular level, were used to trace the potential precursors of CHON. Results show that more than half of the snow CHON molecules may be related to the oxidized and hydrolyzed processes of atmospheric organics. Potential formation processes of atmospheric organics on a molecular level provide a new concept to better understand the sources and scavenging mechanisms of organic nitrogen species in the atmosphere.


New pharmacological perspectives and therapeutic potential of PPAR-gamma agonists.
The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor superfamily has classically been characterized for its implications in adipocyte differentiation and fat metabolism. Recently, PPARgamma has been implicated in the pathophysiology of inflammatory and immune responses possibly through inhibition of the mitogen-activated protein kinase (MAPK) pathways or the activation of the transcription nuclear factor kappa B (NF-kappaB). Thus, these agents might also have therapeutic potential in the treatment of gastrointestinal inflammatory disorders, such as ulcerative colitis and Crohn's disease. The synthetic thiazolidinediones (TZDs), a novel class of insulin-sensitizing drugs, were the first class of compounds identified as PPARgamma ligands, and represent a significant advance in anti-diabetic therapy. However, there is less information about endogenous ligands, although the prostaglandin (PG)J(2) and the oxidized phosphatidylcholine have been suggested. Furthermore, PPARgamma ligands have been shown to be potent inhibitors of angiogenesis, a process necessary for tumor growth and metastasis, and protect against cellular transformation. Further work is needed to establish in detail the anti-proliferative and pro-differentiation mechanisms of PPARgamma activators and their efficacy in certain cancers.


The roles of genetic drift and natural selection in quantitative trait divergence along an altitudinal gradient in Arabidopsis thaliana.
Understanding how natural selection and genetic drift shape biological variation is a central topic in biology, yet our understanding of the agents of natural selection and their target traits is limited. We investigated to what extent selection along an altitudinal gradient or genetic drift contributed to variation in ecologically relevant traits in Arabidopsis thaliana. We collected seeds from 8 to 14 individuals from each of 14 A. thaliana populations originating from sites between 800 and 2700 m above sea level in the Swiss Alps. Seed families were grown with and without vernalization, corresponding to winter-annual and summer-annual life histories, respectively. We analyzed putatively neutral genetic divergence between these populations using 24 simple sequence repeat markers. We measured seven traits related to growth, phenology and leaf morphology that are rarely reported in A. thaliana and performed analyses of altitudinal clines, as well as overall QST-FST comparisons and correlation analyses among pair-wise QST, FST and altitude of origin differences. Multivariate analyses suggested adaptive differentiation along altitude in the entire suite of traits, particularly when expressed in the summer-annual life history. Of the individual traits, a decrease in rosette leaf number in the vegetative state and an increase in leaf succulence with increasing altitude could be attributed to adaptive divergence. Interestingly, these patterns relate well to common within- and between-species trends of smaller plant size and thicker leaves at high altitude. Our results thus offer exciting possibilities to unravel the underlying mechanisms for these conspicuous trends using the model species A. thaliana.


Respiratory muscle activity in patients with COPD walking to exhaustion with and without pressure support.
The function of the diaphragm and other respiratory muscles during exercise in chronic obstructive pulmonary disease (COPD) remains controversial and few data exist regarding respiratory muscle pressure generation in this situation. The inspiratory pressure/time products of the oesophageal and transdiaphragmatic pressure, and the expiratory gastric pressure/time product during exhaustive treadmill walking in 12 patients with severe COPD are reported. The effect of noninvasive positive pressure ventilation during treadmill exercise was also examined in a subgroup of patients (n=6). During free walking, the inspiratory pressure/time products rose early in the walk and then remained level until the patients were forced to stop because of intolerable dyspnoea. In contrast, the expiratory gastric pressure/time product increased progressively throughout the walk. When patients walked the same distance assisted by noninvasive positive pressure ventilation, a substantial reduction was observed in the inspiratory and expiratory pressure/time products throughout the walk. When patients walked with positive pressure ventilation for as long as they could, the pressure/time products observed at exercise cessation were lower than those observed during exercise cessation after free walking. It is concluded that, in severe chronic obstructive pulmonary disease, inspiratory muscle pressure generation does not increase to meet the demands imposed by exhaustive exercise, whereas expiratory muscle pressure generation rises progressively. Inspiratory pressure support was shown to substantially unload all components of the respiratory muscle pump.


Physical exercise and resistive breathing training in severe chronic airways obstruction--are they effective?
Twenty-one patients with severe chronic irreversible airflow obstruction (FEV1 consistently less than 1.2 l) were allocated randomly to one of two training programmes designed to reduce respiratory disability or a placebo training control group. Daily structured physical exercise, twice daily inspiratory muscle training by resistive breathing, or daily placebo training were undertaken for 10 weeks, and the effects on lung function, exercise capacity, respiratory symptoms and psychological state compared. Maximal work achieved on a progressive bicycle exercise test was significantly increased in all groups (36%, 23% and 34% respectively) and global improvement in mood also occurred. There was no significant change in respiratory symptom score, static lung function tests or 12 min walking distance. Neither form of active treatment showed superiority over placebo training.


[Bioresonance therapy (biophysical information therapy) in stuttering children].
This study tried to investigate whether bioresonance therapy could have a beneficial effect in stuttering children of school age who showed no progress under other therapies. The 14 patients, age 9-18 years, were randomized in two groups. The first received 10 sessions of bioresonance, the second continued with speech therapy. In the second phase of the study the first group received speech therapy while the second was treated by bioresonance. The intensity of the stuttering was measured at the beginning, at mid-term and at the end of the 9 months experiment. Various established methods were used for that purpose. It was not possible to demonstrate any improvement of the stuttering during or after either of the two therapies. This study showed how difficult it is to investigate stuttering scientifically. It turned out that in reality there is a lack of precise differential diagnosis. This means that true stuttering can hardly be distinguished from other speech disturbances and is under the influence of countless external factors.


Clinical course of recurrent respiratory papillomatosis in Danish children.
To evaluate the clinical course of juvenile-onset recurrent respiratory papillomatosis (RP) with respect to age, disease duration, and maternal condylomas. Inception cohort study. All ear, nose, and throat departments in public Danish hospitals. Fifty-seven Danish children diagnosed with RP and born between 1974 and 1993 were observed for an average of 14 years after diagnosis. Removal of respiratory papillomas by knife biopsy, laser surgery, or cryotherapy. Children younger than 5 years diagnosed with RP underwent an average of 4.1 surgeries in the first year of disease, the highest rate among all our patients. The overall surgery rate decreased over time after initial diagnosis but remained significantly higher for children with a younger age of onset for the first 4 years of disease (P <.001) and for children with a maternal history of condylomas in pregnancy for years 4 to 10 of the disease (P <.001). We also observed an independent and statistically significant (P <.001) decreasing surgery rate with increasing age and time from initial diagnosis. The trend for children with recurrent disease was a decreasing rate of surgical procedures (28 of 42 patients with recurrent disease); however, a third of patients (14/42) demonstrated a constant or increasing rate of surgical procedures over time. The clinical course of RP is characterized by a high frequency of surgeries soon after diagnosis that diminishes over time and with increasing age. Additional studies are warranted to identify factors associated with cases that do not conform to the usual disease course.


Comparative effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on MCF-7, RL95-2, and LNCaP cells: role of target steroid hormones in cellular responsiveness to CYP1A1 induction.
A study was conducted to investigate whether target hormones affect 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible gene expression, using as an experimental model system three human cancer cell lines, breast (MCF-7), uterine (RL95-2), and prostate (LNCaP). Exposure to TCDD induced the CYP1A1 gene in all three cell lines. MCF-7 and RL95-2 cells showed more than 15- and 10-fold induction of EROD (7-ethoxyresorufin O-deethylase) activity, respectively, compared with the less responsive LNCaP cells. Surprisingly, however, TCDD-induced reporter gene activity driven by a single XRE element was similar in RL95-2 and LNCaP cells. The steady-state levels of expression of aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (ARNT) were similar in all three cell lines. Expression of the CYP1B1 and PAI-2 genes was induced by TCDD in MCF-7 and RL95-2, but not in LNCaP, cells. Transient coexpression of estradiol receptor-alpha (ER-alpha) with a TCDD-responsive reporter plasmid and subsequent TCDD treatment increased responsiveness to TCDD in RL95-2 and LNCaP cells. Treatment with AZA-C, a DNA methyltransferase inhibitor, enhanced responsiveness to TCDD, in terms of EROD activity in LNCaP cells, but not in MCF-7 and RL95-2 cells, suggesting that DNA methylation in the CpG dinucleotide within the XRE core sequence is another factor involved in silencing of CYP1A1 in LNCaP cells. TCDD markedly inhibited E(2)- or testosterone-induced reporter gene activities in all three cell lines. Conversely, these target hormones inhibited TCDD-induced EROD activity in the three cell lines. These findings suggest that TCDD and the target steroid hormones negatively regulate each other's activity.


The mitotic peptidyl-prolyl isomerase, Pin1, interacts with Cdc25 and Plx1.
The cis/trans peptidyl-prolyl isomerase, Pin1, is a regulator of mitosis that is well conserved from yeast to man. Here we demonstrate that depletion of Pin1-binding proteins from Xenopus egg extracts results in hyperphosphorylation and inactivation of the key mitotic regulator, Cdc2/cyclin B. We show biochemically that this phenotype is a consequence of Pin1 interaction with critical upstream regulators of Cdc2/cyclin B, including the Cdc2-directed phosphatase, Cdc25, and its known regulator, Plx1. Although Pin1 could interact with Plx1 during interphase and mitosis, only the phosphorylated, mitotically active form of Cdc25 was able to bind Pin1, an event we have recapitulated using in vitro phosphorylated Cdc25. Taken together, these data suggest that Pin1 may modulate cell cycle control through interaction with Cdc25 and its activator, Plx1.


Zebra fish: an uncharted behavior genetic model.
The zebra fish has been a preferred subject of genetic analysis. It produces a large number of offspring that can be kept in small aquaria, it can be easily mutagenized using chemical mutagens (e.g., ethyl nitrosourea [ENU]), and high-resolution genetic maps exist that aid identification of novel genes. Libraries containing large numbers of mutant fish have been generated, and the genetic mechanisms of the development of zebra fish, whose embryo is transparent, have been extensively studied. Given the extensive homology of its genome with that of other vertebrate species including our own and given the available genetic tools, zebra fish has become a popular model organism. Despite this popularity, however, surprisingly little is known about its behavior. It is argued that behavioral analysis is a powerful tool with which the function of the brain may be studied, and the zebra fish will represent an excellent subject of such analysis. The present paper is a proof of concept study that uses pharmacological manipulation (exposure to alcohol) to show that the zebra fish is amenable to the behavioral genetic analysis of aggression and thus may allow us to reveal molecular mechanisms of this behavioral phenomenon relevant to vertebrates.


UDP-glucose dehydrogenase polymorphisms from patients with congenital heart valve defects disrupt enzyme stability and quaternary assembly.
Cardiac valve defects are a common congenital heart malformation and a significant clinical problem. Defining molecular factors in cardiac valve development has facilitated identification of underlying causes of valve malformation. Gene disruption in zebrafish revealed a critical role for UDP-glucose dehydrogenase (UGDH) in valve development, so this gene was screened for polymorphisms in a patient population suffering from cardiac valve defects. Two genetic substitutions were identified and predicted to encode missense mutations of arginine 141 to cysteine and glutamate 416 to aspartate, respectively. Using a zebrafish model of defective heart valve formation caused by morpholino oligonucleotide knockdown of UGDH, transcripts encoding the UGDH R141C or E416D mutant enzymes were unable to restore cardiac valve formation and could only partially rescue cardiac edema. Characterization of the mutant recombinant enzymes purified from Escherichia coli revealed modest alterations in the enzymatic activity of the mutants and a significant reduction in the half-life of enzyme activity at 37 °C. This reduction in activity could be propagated to the wild-type enzyme in a 1:1 mixed reaction. Furthermore, the quaternary structure of both mutants, normally hexameric, was destabilized to favor the dimeric species, and the intrinsic thermal stability of the R141C mutant was highly compromised. The results are consistent with the reduced function of both missense mutations significantly reducing the ability of UGDH to provide precursors for cardiac cushion formation, which is essential to subsequent valve formation. The identification of these polymorphisms in patient populations will help identify families genetically at risk for valve defects.


Evidence-based venous thromboembolism prophylaxis is associated with a six-fold decrease in numbers of symptomatic venous thromboembolisms in rehabilitation inpatients.
To measure the impact of a standardized risk assessment tool and specialty-specific, risk-adjusted venous thromboembolism (VTE) order sets on compliance with American College of Chest Physicians (ACCP) guidelines and the number of symptomatic VTE as assessed by administrative data. Prospective cohort study. Academic hospital inpatient rehabilitation unit. All patients on the rehabilitation unit. Assessment of VTE risk factors and evaluated admission VTE prophylaxis orders before and after implementation of an ACCP guideline-based, specialty-specific VTE risk assessment, and prophylaxis order set by using a standardized data collection form. Discharge diagnostic codes for VTE and pulmonary embolism were tracked by ICD-9 (International Classification of Diseases, 9th edition) discharge diagnosis codes for the 12 months before and 36 months after the intervention. Before implementation of the VTE order set, 27% of patients received VTE prophylaxis in compliance with the 2004 ACCP VTE guidelines. By following implementation of specialty-specific, risk-adjusted VTE order sets, compliance increased to 98%. In the year before VTE order-set implementation, the number of VTEs per admission was 49 per 1000. By following implementation, the number of VTEs steadily decreased each year to 8 per 1000 in 2007 (χ(2) = 14.985; P = .0001). Implementation of a standardized VTE risk assessment tool and prophylaxis order set resulted in a substantial improvement in compliance with ACCP guidelines for VTE prophylaxis and was associated with a 6-fold reduction in the number of symptomatic VTEs in a hospital-based rehabilitation unit.


Distribution of mercury in the tissues of five species of freshwater fish from Lake Mead, USA.
Total mercury (Hg) concentrations were determined in seven tissues (skeletal muscle, liver, blood, gonad, brain, gill, and heart) of 59 striped bass and four tissues (muscle, liver, blood, and gonad) of 69 largemouth bass, 76 channel catfish, 12 bluegill, and 22 blue tilapia collected from Lake Mead, USA. Mercury levels generally increased according to trophic level and fish length. For striped bass, mean Hg levels (ng g(-1), wet mass) were highest in the liver (531), followed by muscle (309), heart (186), gonad (136), brain (77), gill (52), and blood (36). Similarly, Hg levels in the catfish and tilapia were liver > muscle > gonad > blood. In contrast, largemouth bass and bluegill had the highest levels in muscle, followed by liver, gonad, and blood. Generally, Hg levels were strongly correlated among the tissues, especially for blood/muscle and blood/liver. As the body burden of Hg increased, the concentration in blood and organs increased relative to the concentration in muscle. The trend was most pronounced for the liver. These relationships could form the basis of a predictive model and suggest that blood and muscle (plugs) could be useful for a non-lethal measure of Hg concentration and exposure in fish. For the striped bass, elevated Hg levels in the tissues were also correlated with degree of emaciation. Liver-to-muscle ratios were similar to literature values, except for tilapia with an average ratio of approximately 1.7, which is higher than generally reported for non-piscivores. Finally, this study demonstrates the usefulness of a solid sampling approach in trace element monitoring, especially as pertaining to in vivo analysis, analysis of a large number of samples and reduction of contamination risk.


Contribution of the two conserved tryptophan residues to the catalytic and structural properties of Proteus mirabilis glutathione S-transferase B1-1.
PmGSTB1-1 (Proteus mirabilis glutathione S-transferase B1-1) has two tryptophan residues at positions 97 and 164 in each monomer. Structural data for this bacterial enzyme indicated that Trp97 is positioned in the helix a4, whereas Trp164 is located at the bottom of the helix a6 in the xenobiotic-binding site. To elucidate the role of the two tryptophan residues they were replaced by site-directed mutagenesis. Trp97 and Trp164 were mutated to either phenylalanine or alanine. A double mutant was also constructed. The effects of the replacement on the activity, structural properties and antibiotic-binding capacity of the enzymes were examined. On the basis of the results obtained, Trp97 does not seem to be involved in the enzyme active site and structural stabilization. In contrast, different results were achieved for Trp164 mutants. Conservative substitution of the Trp164 with phenylalanine enhanced enzyme activity 10-fold, whereas replacement with alanine enhanced enzyme activity 17-fold. Moreover, the catalytic efficiency for both GSH and 1-chloro-2,4-dinitrobenzene substrates improved. In particular, the catalytic efficiency for 1-chloro-2,4-dinitrobenzene improved for both W164F (Trp164-->Phe) and W164A by factors of 7- and 22-fold respectively. These results are supported by molecular graphic analysis. In fact, W164A presented a more extensive substrate-binding pocket that could allow the substrates to be better accommodated. Furthermore, both Trp164 mutants were significantly more thermolabile than wild-type, suggesting that the substitution of this residue affects the overall stability of the enzyme. Taken together, these results indicate that Trp164 is an important residue of PmGSTB1-1 in the catalytic process as well as for protein stability.


Polyamines potentiate responses of N-methyl-D-aspartate receptors expressed in xenopus oocytes.
Glutamate, the major excitatory neurotransmitter in the central nervous system, activates at least three types of channel-forming receptors defined by the selective agonists N-methyl-D-aspartate (NMDA), kainate, and quisqualate [or more selectively by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)]. Activation of the NMDA receptor requires glycine as well as NMDA or glutamate. Recent studies have provided evidence that certain polyamines potentiate the binding by NMDA receptors of glycine and the open channel blocker MK-801. To determine whether polyamines alter channel opening, we examined their effects on rat brain glutamate receptors expressed in Xenopus oocytes. Our results demonstrate that spermine potentiates the response of the NMDA receptor but has no effect on responses to kainate and quisqualate. Furthermore, spermine increases the maximum response to NMDA and glycine and acts, at least in part, by increasing the apparent affinity of the NMDA receptor/channel complex for glycine. The present findings and the fact that polyamines are a natural constituent of brain suggest that polyamines may play a role in the regulation of glutamatergic transmission.


Frugivory and seed dispersal by birds in Cereus jamacaru DC. ssp. jamacaru (Cactaceae) in the Caatinga of Northeastern Brazil.
Studies of the dispersal modes of plants aid our understanding of the dynamics of resource and its availability for dispersal agents. The present work sought to characterize the fruiting patterns of the native Caatinga (dryland) cactus Cereus jamacaru, identify its principal dispersers, and evaluate the effects of seed passage through digestive tract of dispersers on its germination. Cereus jamacaru present an annual fruiting pattern and fruiting peaks occurred during June/2009 and February/2010. A total of 135 visits by nine species of resident Caatinga bird species were recorded. The most frequent visiting bird species were Paroaria dominicana and Euphonia chlorotica. Length of bird visits varied from 15 seconds to 4 minutes and seeds removed by birds travelled 10.6 ± 11.2 m until dispersers make the first landing perch, in some cases more than 40 meters away. Germination tests show birds had a high quantity of viable seeds of C. jamacaru in its feces. Seeds that passed through the digestive tract of birds showed a similar germinability of the seeds of the control group. However, the seeds dispersed by birds showed lowest mean germination time related to the control group seeds. This study highlights the potential role of birds as seed dispersers of C. jamacaru, swallowing the whole seeds and defecating intact seeds, accelerating the germination process and transporting seeds away from the mother plant.


Structural Insights into the Eukaryotic Transcription Initiation Machinery.
Eukaryotic gene transcription requires the assembly at the promoter of a large preinitiation complex (PIC) that includes RNA polymerase II (Pol II) and the general transcription factors TFIID, TFIIA, TFIIB, TFIIF, TFIIE, and TFIIH. The size and complexity of Pol II, TFIID, and TFIIH have precluded their reconstitution from heterologous systems, and purification relies on scarce endogenous sources. Together with their conformational flexibility and the transient nature of their interactions, these limitations had precluded structural characterization of the PIC. In the last few years, however, progress in cryo-electron microscopy (cryo-EM) has made possible the visualization, at increasingly better resolution, of large PIC assemblies in different functional states. These structures can now be interpreted in near-atomic detail and provide an exciting structural framework for past and future functional studies, giving us unique mechanistic insight into the complex process of transcription initiation.


Effect of femoral stem centralizer design on cement mantle porosity.
We studied whether prosthetic femoral stem centralizers have a detrimental effect on the macroporosity of the cement mantle. With pressure and time monitoring identically cast, moulded prosthetic femora had Charnley C-stems implanted. The stems were removed and the cement mantle was sectioned and photographed to record the size and location of voids (macropores). Cement voids were found in 85% of femora when a centralizer was used compared to 20% of the control group (p=0.002). A modular centralizer produced cement voids of a larger volume and more frequent occurrence (p=0.002). The macroporosity of the cement mantle was independent of the rate of implantation (p=0.39). Modern distal stem centralizers therefore increase the incidence of void formation in the cement mantle; although they help guard against malposition of the implant, they may have implications for early loosening.


Eco-evolutionary feedbacks among pollinators, herbivores, and their plant resources.
Eco-evolutionary feedbacks among multiple species occur when one species affects another species' evolution via its effects on the abundance and traits of a shared partner species. What happens if those two species enact opposing effects on their shared partner's population growth? Furthermore, what if those two kinds of interactions involve separate traits? For example, many plants produce distinct suites of traits that attract pollinators (mutualists) and deter herbivores (antagonists). Here, we develop a model to explore how pollinators and herbivores may influence each other's interactions with a shared plant species via evolutionary effects on the plant's nectar and toxin traits. The model results predict that herbivores indirectly select for the evolution of increased nectar production by suppressing plant population growth. The model also predicts that pollinators indirectly select for the evolution of increased toxin production by plants and increased counterdefenses by herbivores via their positive effects on plant population growth. Unless toxins directly affect pollinator foraging, plants always evolve increases in attraction and defense traits when they interact with both kinds of foragers. This work highlights the value of incorporating ecological dynamics to understand the entangled evolution of mutualisms and antagonisms in natural communities.


Self-efficacy and diabetes prevention in overweight South Asians with pre-diabetes.
We evaluated the effects of a diabetes prevention itervention on self-efficacy (SE) and the associations between SE and diabetes-related outcomes among overweight Asian Indian adults with pre-diabetes in a randomized controlled translational trial (the Diabetes Community Lifestyle Improvement Program, D-CLIP). Data were obtained from 550 adults who were randomized to a diabetes prevention program or standard of care. Dietary and exercise-related SEs were measured at baseline, core intervention completion (4 months), and annually until the end of follow-up (3 years or diabetes diagnosis). Mixed-effects regressions described changes in SE over time by treatment group. Among treatment participants, multivariable-adjusted models described associations of SE at baseline and intervention completion with diabetes incidence and other secondary outcomes (weight, waist circumference (WC), exercise, and energy intake). From baseline to 4 months, dietary (β=10.3, p=0.04) and exercise (β=0.49, p=0.04) SE increased significantly in the treatment arm only; however, this increase from baseline was no longer significant at later time points. Among treatment participants, there was no association of dietary or exercise SE with diabetes incidence, but baseline exercise SE was independently associated with improved weight, WC, and exercise at 4 months (p<0.05). Change in exercise SE from baseline to intervention completion also predicted increased exercise at 4, 12, and 24 months (p<0.05). Exposure to D-CLIP resulted in improved SE at treatment completion, but this effect was not sustained over longer follow-up. Several short-term and long-term secondary outcomes, but not diabetes risk, were significantly associated with exercise SE, suggesting this psychosocial trait may facilitate success in achieving certain health goals. NCT01283308.


Construction of social value or utility-based health indices: the usefulness of factorial experimental design plans.
Global indices, which aggregate multiple health or function attributes into a single summary indicator, are useful measures in health research. Two key issues must be addressed in the initial stages of index construction from the universe of possible health and function attributes, which ones should be included in a new index? and how simple can the statistical model be to combine attributes into a single numeric index value? Factorial experimental designs were used in the initial stages of developing a function index for evaluating a program for the care of young handicapped children. Beginning with eight attributes judged important to the goals of the program by clinicians, social preference values for different function states were obtained from 32 parents of handicapped children and 32 members of the community. Using category rating methods each rater scored 16 written multi-attribute case descriptions which contained information about a child's status for all eight attributes. Either a good or poor level of each function attribute and age 3 or 5 years were described in each case. Thus, 2(8) = 256 different cases were rated. Two factorial design plans were selected and used to allocate case descriptions to raters. Analysis of variance determined that seven of the eight clinician selected attributes were required in a social value based index for handicapped children. Most importantly, the subsequent steps of index construction could be greatly simplified by the finding that a simple additive statistical model without complex attribute interaction terms was adequate for the index. We conclude that factorial experimental designs are an efficient, feasible and powerful tool for the initial stages of constructing a multi-attribute health index.


Optimization of steam explosion as a method for increasing susceptibility of sugarcane bagasse to enzymatic saccharification.
The technique of autohydrolysis steam explosion was examined as a means for pretreatment of sugarcane bagasse. Treatment conditions were optimized so that following enzymatic hydrolysis, pretreated bagasse would give 65.1 g sugars/100 g starting bagasse. Released sugars comprised 38.9 g glucose, 0.6 g cellobiose, 22.1 g xylose, and 3.5 g arabinose, and were equivalent to 83% of the anhydroglucan and 84% of the anhydroxylan content of untreated bagasse. Optimum conditions were treatment for 30 S with saturated steam at 220 degrees C with a water-to-solids ratio of 2 and the addition of 1 g H(2)SO(4)/100 g dry bagasse. Bagasse treated in this manner was not inhibitory to fermentation by Saccharomyces uvarum except at low inoculum levels when fermentation time was extended by up to 24 h. Pretreated saccharified bagasse was inhibitory to Pachysolen tannophilus and this was attributed to the formation of acetate from the hydrolysis of acetyl groups present in hemicellulose. The major advantage of the pretreatment is the achievement of high total sugar yield with moderate enzyme requirement and only minor losses due to sugar decomposition.


Relationship between the expression of various markers and prognostic factors in breast cancer.
The immunohistochemical detection of six markers of breast cancer has been compared in the present study with known prognostic factors of the disease to establish locally a standard panel of markers for the management of breast cancer. Sections of tissue of 114 consecutive breast cancer cases were studied immunohistochemically, using antibodies against oestrogen receptor (ER), progesterone receptor (PR), androgen receptor, c-erbB2, cathepsin D, and cyclin D. Marker labelling was graded as recommended in the literature. Using the chi(2)-test, relationships were determined between marker labelling and histological type of cancer, tumour grade, tumour size, axillary lymph node status and age of patient. A p value below 0.05 was considered significant. A positive relationship was found between ER and PR and lower grades of cancer, and a negative relationship was found with medullary and atypical medullary carcinoma. The four other markers showed no relationship with grade or type of cancer. All markers showed no significant relationship with size of tumour, presence of axillary node metastasis or age of patient. There was positive correlation between c-erbB2 and cathepsin D. Our study confirms the association between ER and PR and histological type and grade of breast cancer, both known parameters of good prognosis. We found no consistent relationship between the other four markers and prognostic factors studied, other than the suggestion that c-erbB2 and cathepsin D may be useful markers for poor prognosis and can be usefully applied locally, especially in the light of the current availability of trastuzumab (Herceptin) for management of c-erbB2-positive cases. We found no relationship between the markers and tumour size, axillary lymph node status or age.


Potassium and Humic Acid Synergistically Increase Salt Tolerance and Nutrient Uptake in Contrasting Wheat Genotypes through Ionic Homeostasis and Activation of Antioxidant Enzymes.
Salinity limits the growth and nutrient uptake in crop species. Studies show that both potassium (K) and humic acid (HA) improved plant tolerance to salinity. However, the interactive effect of K and HA on plant tolerance to salinity stress remains unknown. This pot study examined the effect of application of K (0, 5 or 10 mM) and HA (0 or 2 g kg-1), alone or in combination, on the growth and physiology under salinity (100 mM NaCl) in two wheat genotypes (SARC 1, salt tolerant; and SARC 5, salt sensitive). The results revealed that salt stress reduced shoot biomass by 35% and 49% in SARC 1 and SARC 5, respectively. Salinity induced overproduction of H2O2 and lipid peroxidation in both genotypes, but the decline in pigments and stomatal conductance was more profound in SARC 5 than in SARC 1. Combined application of 10 mM K and HA was most effective in alleviating salt stress with improved plant biomass by 47% and 43% in SARC 1 and SARC 5, respectively. Combined application of 10 mM K and HA mitigated salt and induced oxidative stress with the activities of APX, CAT, POD and SOD increased by up to 2.8 folds in SARC 1, and by upto 2.5 folds in SARC 5, respectively. Root and shoot Na contents were increased, while K, Fe and Zn contents were decreased under saline conditions. HA combined with K decreased Na and increased K, Fe and Zn contents in both genotypes. Combined application of 10 mM K and HA was more promising for increasing wheat salt tolerance and nutrient uptake and genotype SARC 1 performed better than SARC 5 for cultivation on saline soils.


Unsupervised Feature Representation of Sleep EEG Data with Transient Deep Boltzmann Machine.
The supervised sleep staging methods are challenged by their strict requirements of a labelled and large dataset. This study considers an unsupervised dimensionality reduction method, the Deep Boltzmann Machine (DBM), trained to a transient state for binary classification of sleep stages. First, the joint time-frequency domain features from the polysomnographic recordings are extracted. Second, the extracted features are smoothed using 2 min rolling window to include contextual temporal information, and finally, they serve as an input for unsupervised training of DBM_transient. The results show that our method effectively separates the sleep stages in two-dimensional feature space with a large Fisher's discriminant value. The classification performance by the DBM_transient achieves a 96.1% F1 score, which is higher than DBM converged to an equilibrium state (95.2%), Principal Component Analysis (92.5%), Isometric Feature Mapping (95.9%), t-distributed Stochastic Neighbor Embedding (94.9%), and Uniform Manifold Approximation (95.0%) on the widely used sleep-EDF database. Additionally, Fisher's discriminant function demonstrates the superiority of the DBM_transient. The significance of the DBM transient lies in its ease of interpretability in two-dimensional space, and future multi-class implementation of the method may facilitate its usage in clinical applications.


Updates of mTOR inhibitors.
Mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism and angiogenesis. mTOR signaling is often dysregulated in various human diseases and thus attracts great interest in developing drugs that target mTOR. Currently it is known that mTOR functions as two complexes, mTOR complex 1/2 (mTORC1/2). Rapamycin and its analogs (all termed rapalogs) first form a complex with the intracellular receptor FK506 binding protein 12 (FKBP12) and then bind a domain separated from the catalytic site of mTOR, blocking mTOR function. Rapalogs are selective for mTORC1 and effective as anticancer agents in various preclinical models. In clinical trials, rapalogs have demonstrated efficacy against certain types of cancer. Recently, a new generation of mTOR inhibitors, which compete with ATP in the catalytic site of mTOR and inhibit both mTORC1 and mTORC2 with a high degree of selectivity, have been developed. Besides, some natural products, such as epigallocatechin gallate (EGCG), caffeine, curcumin and resveratrol, have been found to inhibit mTOR as well. Here, we summarize the current findings regarding mTOR signaling pathway and review the updated data about mTOR inhibitors as anticancer agents.


Acid hydrolysis of cellulose as the entry point into biorefinery schemes.
Cellulose is a major source of glucose because it is readily available, renewable, and does not compete with the food supply. Hydrolysis of cellulose is experiencing a new research and development cycle in which this reaction is carried out over solid catalysts and coupled to other reactions for increased efficiency. Cellulose is typically not soluble in conventional solvents and very resistant to chemical and biological transformations. This Review focuses on aspects related to the hydrolysis of cellulose as this process is a significant entry point into the biorefinery scheme based on carbohydrates for the production of biofuels and biochemicals. Structural features of cellulose, conventional acid-catalyzed reactions, and the use of solid acid catalysts for hydrolysis are discussed. The longterm success of the biorefinery concept depends on the development of energetically efficient processes to convert cellulose directly or indirectly into biofuels and chemicals.


Epoxyeicosatrienoic acids prevent cisplatin-induced renal apoptosis through a p38 mitogen-activated protein kinase-regulated mitochondrial pathway.
Soluble epoxide hydrolase (sEH) catalyzes the conversion of epoxyeicosatrienoic acids into less active eicosanoids, and inhibitors of sEH have anti-inflammatory and antiapoptotic properties. Based on previous observations that sEH inhibition attenuates cisplatin-induced nephrotoxicity by modulating nuclear factor-κB signaling, we hypothesized that this strategy would also attenuate cisplatin-induced renal apoptosis. Inhibition of sEH with AR9273 [1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea)] reduced cisplatin-induced apoptosis through mechanisms involving mitochondrial apoptotic pathways and by reducing reactive oxygen species. Renal mitochondrial Bax induction following cisplatin treatment was significantly decreased by treatment of mice with AR9273 and these antiapoptotic effects involved p38 mitogen-activated protein kinase signaling. Similar mechanisms contributed to reduced apoptosis in Ephx2(-/-) mice treated with cisplatin. Moreover, in pig kidney proximal tubule cells, cisplatin-induced mitochondrial trafficking of Bax and cytochrome c, caspase-3 activation, and oxidative stress are significantly attenuated in the presence of epoxyeicosatrienoic acids (EETs). Collectively, these in vivo and in vitro studies demonstrate a role for EETs in limiting cisplatin-induced renal apoptosis. Inhibition of sEH represents a novel therapeutic strategy for protection against cisplatin-induced renal damage.


Association of low diastolic blood pressure with cardiovascular outcomes and all-cause mortality: A meta-analysis.
Reduction of diastolic blood pressure (DBP) below 70 mmHg may decrease perfusion to the heart and worsen cardiovascular (CV) outcomes. Explore the association between low DBP and CV outcomes. We searched the online databases until August 2023 for studies reporting the risk of all-cause mortality (ACM) or CV outcomes in patients with low versus normal DBP (70-80mm Hg). Inclusion of 10 studies (n = 1,998,223 patients) found that a mean achieved DBP < 60 mmHg was associated with an increased risk of all-cause mortality (HR 1.48; 95 % CI [1.26-1.74]), especially in patients with pre-existing CV disease. It was also associated to a higher risk of major adverse cardiovascular events (HR 1.84; [1.28-2.65]) and myocardial infarction (HR 1.49; [1.13-1.97]). A DBP of 60-69 mmHg was associated with an increased risk of all-cause mortality (HR 1.11; [1.03-1.20]). Reduction of DBP, particularly below 60 mmHg, is associated with increased risk of ACM.


[Applied anatomy study and clinical application of great saphenous veno-saphenous neurocutaneous vascular flap].
To provide the anatomic basis for defect repair of the knee, leg, foot and ankle with great saphenous veno-saphenous neurocutaneous vascular island flaps. The origin, diameter, branches, distribution and anastomoses of the saphenous artery and saphenous neurocutaneous vascular were observed on 20 sides of adult leg specimens and 4 fresh cadaver voluntary legs. Another 4 fresh cadaver voluntary legs were radiographed with a soft X-ray system after the intravenous injection of Vermilion and cross-sections under profound fascial, other hand, micro-anatomic examination was also performed in these 4 fresh cadaver legs. The soft tissue defects in lower extremity, upper extremity, heel or Hucou in hand were repaired with the proximal or distal pedicle flaps or free flaps in 18 patients (12 males and 6 females,aging from 7 to 53 years). The defect was caused by trauma, tumour, ulcer and scar. The locations were Hucou (1 case), upper leg (3 cases), lower extremity and heal (14 cases). Of then, 7 cases were complicated by bone exposure, 3 cases by tendon exposure and 1 case by steel espouse, the defect size were 4 cm x 4 cm to 7 cm x 13 cm. The flap sizes were 4 cm x 6 cm to 8 cm x 15 cm, which pedicle length was 8-11 cm with 2.5-4.0 cm fascia and 1-2 cm skin at width. Genus descending genicular artery began from 9.33 +/- 0.81 cm away from upper the condyles medialis, it branched saphenous artery accompanying saphenous nerve descendent. And saphenous artery reached the surface of the skin 7.21 +/- 0.82 cm away from lower the condyles medialis, and anastomosed with the branches of tibialis posterior artery, like "Y" or "T" pattern. The chain linking system of arteries were found accompanying along the great saphenous vein as saphenous nerve, and then a axis blood vessel was formed. The small artery of only 0.05-0.10 mm in diameter, distributed around the great saphenous vein within 5-8 mm and arranged parallelly along the vein like water wave in soft X-ray film. All proximal flaps, distal pedicle flaps and free flaps survived well. The appearance, sensation and function were satisfactory in 14 patients after a follow-up of 6-12 months. The great saphenous vein as well as saphenous neurocutaneous has a chain linking system vascular net. A flap with the vascular net can be transplanted by free, by reversed pedicle, or by direct pedicle to repair the wound of upper leg and foot. A superficial vein-superficial neurocutaneous vascular flap with abundance blood supply and without sacrificing a main artery is a favourite method in repair of soft tissue defects in foot and lower extremity.


Endothelin receptors mediating vasoconstriction in rat pressurized small arteries.
The effects of endothelin-1 (ET-1), a nonselective ETA and ETB receptor agonist, and sarafotoxin S6c, a selective ETB agonist, were investigated in the presence and absence of BQ123 and BQ788, ETA- and ETB-selective antagonists, respectively, in rat mesenteric small arteries, using a perfusion pressurized arteriograph in which segments of vessels were cannulated and exposed to constant pressure and flow. ET-1 (10(-13)-10(-7) M) induced vasoconstriction in both intact and endothelium-denuded arteries in a concentration-dependent manner. BQ123 (10(-7) and 10(-6) M) inhibited the effect of ET-1, displacing the concentration-response curve to the right in a concentration-dependent manner. The effect of ET-1 was not significantly affected by BQ788 (10(-7) and 10(-6) M), a selective antagonist of ETB receptors. Sarafotoxin S6c (10(-11)-10(-7) M) also induced a slight concentration-dependent vasoconstriction. The effect of sarafotoxin S6c (10(-8) M) was inhibited by the ETB-selective antagonist BQ788 (10(-7) M), but was not significantly changed by BQ123 (10(-7) M). Vasoconstriction induced by sarafotoxin S6c (10(-8) M) in a single bolus concentration was significantly greater than the contraction induced by the same concentration as part of a cumulative concentration-response curve, indicating desensitization or downregulation of ETB receptors during the latter. Repeated application of single concentrations of sarafotoxin S6c (10(-8) M) caused progressively smaller contraction of arteries. These results show the existence of both ETA and ETB vasoconstrictor receptors located on smooth muscle of small arteries. They also show that ETB receptors induce a smaller constrictor effect, and rapidly undergo desensitization after sustained or repeated activation.


[Comparative study of the effect of paracetamol, phenacetin and amidopyrine on mitochondrial function in isolated rat hepatocytes].
Effects of amidopyrine, phenacetin and paracetamol on the viability and energetic state of isolated rat hepatocytes were compared. During incubation in minimal salt solution all drugs in concentrations above 1 mM in dose-dependent manner decreased the viability of hepatocyte suspension assessed by trypan blue dye inclusion and inhibited the ATP synthesis and the respiratory activity. Cytotoxic effect of chemicals decrease in the order: amidopyrine-->phenacetin-->paracetamol. The inhibition of the rate of endogenous respiration were accompanied by stimulation of oxygen consumption in nonmitochondrial systems. An uncoupler of oxidative phosphorylation, 2,4-dinitrophenol, and disruption of plasma membrane by digitonin followed by substrate succinate addition did not restore the respiratory activity of hepatocytes up to the level of control cells. These data show that cytotoxicity of the chemicals is determined by their interaction with enzymes of mitochondrial respiratory chain.


The inverse benefit law: how drug marketing undermines patient safety and public health.
Recent highly publicized withdrawals of drugs from the market because of safety concerns raise the question of whether these events are random failures or part of a recurring pattern. The inverse benefit law, inspired by Hart's inverse care law, states that the ratio of benefits to harms among patients taking new drugs tends to vary inversely with how extensively the drugs are marketed. The law is manifested through 6 basic marketing strategies: reducing thresholds for diagnosing disease, relying on surrogate endpoints, exaggerating safety claims, exaggerating efficacy claims, creating new diseases, and encouraging unapproved uses. The inverse benefit law highlights the need for comparative effectiveness research and other reforms to improve evidence-based prescribing.


Selective inhibition of the NLRP3 inflammasome protects against acute ethanol-induced cardiotoxicity in an FBXL2-dependent manner.
Binge drinking exerts cardiac toxicity through various mechanisms, including oxidative stress and inflammation. NLRP3 inflammasomes possess both pro- and anti-inflammatory properties, although the role of NLRP3 in ethanol-induced cardiotoxicity remains unknown. This study is designed to examine the role of NLRP3 inflammasome in acute ethanol cardiotoxicity and the underlying mechanisms of action. Nine- to twelve-week-old adult male C57BL/6 mice are administered with ethanol (1.5 g/kg, twice daily, i.p.) for 3 days. A cohort of control and ethanol-challenged mice are treated with the NLRP3 inhibitor MCC950 (10 mg/kg/day, i.p., days 1 and 3). Myocardial geometry and function are monitored using echocardiography and cardiomyocyte edge-detection techniques. Levels of NLRP3 inflammasome, mitophagy and apoptosis are evaluated by western blot analysis and immunofluorescence techniques. Acute ethanol challenge results in abnormally higher cardiac systolic function, in conjunction with deteriorated cardiac diastolic function and cardiomyocyte contractile function. Levels of NLRP3 inflammasome and apoptosis are elevated, and mitophagy flux is blocked (elevated Pink1-Parkin and LC3B along with diminished p62 and Rab7) in mice receiving acute ethanol challenge. Although MCC950 does not elicit a notable effect on myocardial function, apoptosis or inflammasome activation in the absence of ethanol exposure, it effectively rescues acute ethanol cardiotoxicity, as manifested by restored myocardial and cardiomyocyte functional homeostasis, suppressed NLRP3 inflammasome activation and apoptosis, and improved mitophagy flux. Our data further suggest that FBXL2, an E3 ubiquitin ligase associated with mitochondrial homeostasis and mitophagy, is destabilized due to proteasomal degradation of caspase-1 by ethanol-induced hyperactivation of NLRP3-caspase-1 inflammasome signaling, resulting in mitochondrial injury and apoptosis. These findings denote a role for NLRP3 inflammasome in acute ethanol exposure-induced cardiotoxicity in an FBXL2-dependent manner and the therapeutic promise of targeting NLRP3 inflammasome for acute ethanol cardiotoxicity.


Experiences of Infant and Child Care of Mothers with Disabilities in Turkey: A Qualitative Study.
Mothers with disabilities have difficulties fulfilling their gender and motherhood roles. The purpose of this study was to determine the infant and child care-related experiences of mothers with disabilities in Turkey. A conventional content analysis was used in this qualitative design. Fourteen mothers with disabilities participated in semi-structured in-depth interviews consisting of open-ended questions about their infant and child care experiences. Three themes and eight subthemes emerged from the data analysis. The themes were: role fulfillment, barriers, and coping and support. All of the women said that they wanted to become mothers, and when they did so, they felt they had fulfilled their roles in society. However, there was a societal misconception that woman with disabilities 'could not give birth to children or would not properly care for them. Measures should be taken to eliminate negative social perceptions of mothers with disabilities. Public support should be provided to meet the needs of mothers with disabilities.


[Walking recovery in stroke patients with femoral fracture].
The aims of this study were: 1) to evaluated the degree of walking of hemiplegic patients after femur fracture, 2) to evaluate if the neurological damage interferes with the recovery of walking. We studied 51 hemiplegic patients with femur fracture. All patients could walk without any help before the fracture. At the end of the rehabilitation period we had the following results: 5.8% of patients regained full walking independence; 37.2% walked with a cane; 43.1% with a quadripod; 9.8% walked with assistance; 3.9% remained unable to walk. 50.9% of them regained their prefracture functions. 96.1% returned directly to their own home, the remaining 3.9% were admitted to Geriatric hospitals. To address the second aim, we divided the same patients into two groups of 20 patients each (A = mild impairment; B = severe impairment) according to Mathew's scale. At the end of treatment, 95% of group A and 75% of group B regained full walking independence. 1) the femur fracture did not influence the recovery of walking in stroke patients, 2) patients with mild neurological impairment had enhanced recovery of walking.


Antibiotics, gut microbiome and obesity.
Antibiotics have been hailed by many as "miracle drugs" that have been effectively treating infectious diseases for over a century, leading to a marked reduction in morbidity and mortality. However, with the increasing use of antibiotics, we are now faced not only with the increasing threat of antibiotic resistance, but also with a rising concern about potential long-term effects of antibiotics on human health, including the development of obesity. The obesity pandemic continues to increase, a problem that affects both adults and children alike. Disruptions to the gut microbiome have been linked to a multitude of adverse conditions, including obesity, type 2 diabetes, inflammatory bowel diseases, anxiety, autism, allergies, and autoimmune diseases. This review focuses on the association between antibiotics and obesity, and the role of the gut microbiome. There is strong evidence supporting the role of antibiotics in the development of obesity in well-controlled animal models. However, evidence for this link in humans is still inconclusive, and we need further well-designed clinical trials to clarify this association.


Ecology and evolution of cycad-feeding Lepidoptera.
Cycads are an ancient group of tropical gymnosperms that are toxic to most animals - including humans - though the larvae of many moths and butterflies (order: Lepidoptera) feed on cycads with apparent immunity. These insects belong to distinct lineages with varying degrees of specialisation and diverse feeding ecologies, presenting numerous opportunities for comparative studies of chemically mediated eco-evolutionary dynamics. This review presents the first evolutionary evaluation of cycad-feeding among Lepidoptera along with a comprehensive review of their ecology. Our analysis suggests that multiple lineages have independently colonised cycads from angiosperm hosts, yet only a few clades appear to have radiated following their transitions to cycads. Defensive traits are likely important for diversification, as many cycad specialists are warningly coloured and sequester cycad toxins. The butterfly family Lycaenidae appears to be particularly predisposed to cycad-feeding and several cycadivorous lycaenids are warningly coloured and chemically defended. Cycad-herbivore interactions provide a promising but underutilised study system for investigating plant-insect coevolution, convergent and divergent adaptations, and the multi-trophic significance of defensive traits; therefore the review ends by suggesting specific research gaps that would be fruitfully addressed in Lepidoptera and other cycad-feeding insects.


The South American lungfish Lepidosiren paradoxa as a new host for Trichodina quelenii.
Recently, the South American lungfish Lepidosiren paradoxa is being found inside aquaculture ponds, and even though there are a few studies on their parasite fauna, there is still much to be reported. Thus, the objective of this study is to report parasitism by trichodinids in L. paradoxa, as these ciliate protozoa are related to injuries and mortality in fish farming. The lungfish were collected from experimental tanks, had their tegument scraped and the resultant mucus was analyzed under an optical microscope for morphological and morphometrical analyses in Giemsa and silver nitrate stained slides. The species found was identified as Trichodina quelleni. This is the first report of this parasite in L. paradoxa, and the second report in cultivated fish in Brazil.


Polyomavirus-associated nephropathy: a comparison of 2 different strategies for immunosuppression reduction.
Polyomavirus-associated nephropathy (PVAN) is an increasing cause of renal allograft dysfunction, but the optimal management of immunosuppression for these patients is unclear. We examined the clinical course of 58 patients with biopsy-proven PVAN diagnosed from 1997 to 2008 at Johns Hopkins Medical Institutions. Immunosuppression management was analyzed as 2 different immunosuppression reduction strategies, the first centered on eliminating a single immunosuppressive drug and reducing the doses of all other immunosuppressive drugs (Strategy A, n = 40), compared with the second, centered on reducing the doses of all immunosuppressive drugs and eliminating none (Strategy B, n = 18). Primary outcome was graft failure, defined as a 50% reduction in estimated glomerular filtration rate, or the need for dialysis within 2 years of PVAN diagnosis. Graft failure developed in 17 (29%) patients during follow-up. In unadjusted and adjusted Cox models, both strategies of immunosuppression reduction had similar efficacy in preventing graft failure (hazard ratio [HR], 0.61; 95% confidence interval, 0.18-2.06; p = 0.43). Rejection after PVAN occurred in 24 of 58 patients and was associated with a 3-fold higher risk of graft failure (HR, 2.99; p = 0.005). Ancillary therapies (cidofovir or leflunomide) were associated with a trend toward faster clearance of viremia (p = 0.65) but were not predictive of outcome.In conclusion, the 2 strategies of immunosuppression reduction had similar efficacy in preventing graft failure. Post-PVAN rejection leads to graft failure. Early repeat allograft biopsy should be considered in the management of PVAN with persistent graft dysfunction.


Cardiac rehabilitation after myocardial infarction: what influences patients' intentions to attend?
Cardiac rehabilitation (CR) programmes have increased their availability and expanded their eligibility criteria. This study sought to identify current predictors and reasons influencing myocardial infarction patients' pre-discharge intentions to attend CR. Patients in this longitudinal, prospective, five site study completed questionnaires that surveyed their intentions to attend, attendance and main reasons for non-attendance at CR. 84% of the 1172 patients indicated that they intended to attend CR. Multivariate analyses revealed that age, employment and earlier history of myocardial infarction were significant predictors of intention to attend CR, yet contributed to only a small proportion of the variance. The main reasons given for not intending to attend CR were lack of interest and perception that the programme would not be beneficial. Other obstacles included work, transport or time. A total of 708 (60%) patients responded at 12 months, and of these, 44% who did not intend to attend CR had attended. Patient sociodemographic and clinical profile, although significant, are not major predictors of intention to attend CR. Lack of interest and misconceptions regarding CR are cited as key barriers. Some of these seem to have been addressed post discharge as a good proportion of patients who had not intended to attend CR did change their minds and attended. Motivation of patients to participate in CR, including the identification of barriers and the provision of comprehensive information about the purpose and varied formats of CR programmes, could be used to help further address barriers to attendance.


Ac4C Enhances the Translation Efficiency of Vegfa mRNA and Mediates Central Sensitization in Spinal Dorsal Horn in Neuropathic Pain.
N4-Acetylcytidine (ac4C), a highly conserved post-transcriptional machinery with extensive existence for RNA modification, plays versatile roles in various cellular processes and functions. However, the molecular mechanism by which ac4C modification mediates neuropathic pain remains elusive. Here, it is found that the enhanced ac4C modification promotes the recruitment of polysome in Vegfa mRNA and strengthens the translation efficiency following SNI. Nerve injury increases the expression of NAT10 and the interaction between NAT10 and Vegfa mRNA in the dorsal horn neurons, and the gain and loss of NAT10 function further confirm that NAT10 is involved in the ac4C modification in Vegfa mRNA and pain behavior. Moreover, the ac4C-mediated VEGFA upregulation contributes to the central sensitivity and neuropathic pain induced by SNI or AAV-hSyn-NAT10. Finally, SNI promotes the binding of HNRNPK in Vegfa mRNA and subsequently recruits the NAT10. The enhanced interaction between HNRNPK and NAT10 contributes to the ac4C modification of Vegfa mRNA and neuropathic pain. These findings suggest that the enhanced interaction between HNRNPK and Vegfa mRNA upregulates the ac4C level by recruiting NAT10 and contributes to the central sensitivity and neuropathic pain following SNI. Blocking this cascade may be a novel therapeutic approach in patients with neuropathic pain.


Trials of an inactivated equid herpesvirus 1 vaccine: challenge with a subtype 2 virus.
Serological responses following two and three doses of an inactivated equid herpesvirus 1 ( EHV -1) vaccine containing a subtype 1 strain were examined in yearling ponies. Complement fixing antibody responses were significantly higher against the subtype 1 vaccine strain than against a subtype 2 virus. Complement fixing antibody responses declined rapidly after the second dose of vaccine and had returned to almost pre-vaccination levels eight weeks after the second dose of vaccine. Complement fixing antibody titres to the heterologous subtype 2 strain increased after each successive dose of vaccine. The neutralising antibody responses following vaccination were weak although less strain specific than the complement fixing antibody responses. When challenged with a subtype 2 strain, 15 ponies which had received three doses of vaccine, two, eight and 12 weeks previously resisted challenge infection. However, 11 out of 15 ponies which had received two doses of vaccine eight and 12 weeks previously were susceptible to infection. While two doses of vaccine did not reduce duration of virus excretion or febrile responses in ponies challenged eight weeks after the second dose, the amount of virus excreted was significantly reduced.


Guidelines for international collaborative research.
As the global village becomes a reality, there is an increasing need to conduct international collaborative studies in family practice. A workshop at the WONCA meeting in Hong Kong used international attendees to produce a set of guidelines for international research. At the workshop four completed international projects, each using a different strategy, were presented so that common themes might become apparent. The themes were then discussed and guidelines emerged from the process. Seven guidelines emerged for consideration before embarking on an international collaborative research project in family medicine. The guidelines deal with the characteristics of the research question and the importance of communication. The need for simple, brief methods of data collection, funding and pilot testing were identified. The question must be relevant to all participants to maintain interest and measurement tools must be validated to understand the impact of cultural differences in understanding.


The evolution of external quality evaluation: observations from the Joint Commission on Accreditation of Healthcare Organizations.
The Joint Commission on Accreditation of Healthcare Organizations, the oldest health care accrediting body in the world, currently accredits almost 20000 organizations in the USA. Although continuing to be professionally-sponsored, accreditation's rapid growth in recent years has been driven by the external users of accreditation--government, purchasers, and public--rather than by the original users, the professionals themselves. This experience in the USA suggests that over time successful external quality evaluation mechanisms throughout the world will involve representatives of the public, purchasers, and government in establishing standards and setting policies. Without this involvement, these stakeholders are unlikely to find the mechanisms credible in addressing their needs, and will seek alternatives--adding cost and duplication to the external quality evaluation system. Successful mechanisms are also likely to provide more detailed information about an organization's performance to the public, purchasers, and the government, while creating evaluation processes that provide for innovation and support improvement in efficiency, as well as quality, through incorporation of aspects of the Baldrige and European Foundation for Quality Management approaches to organizational excellence. Finally, successful evaluation mechanisms are likely to create a special focus on the safety of care, incorporating aspects of the International Organization for Standardization's ISO 9000 approach to quality management. While the specific nature, priority, and timing of these changes will differ from country to country, they are likely to influence the evolution of external quality evaluation throughout the world. External evaluation of health care organizations' quality holds great promise, but its long-term success depends on responding to all those who will want to depend on it.


Tuba Activates Cdc42 during Neuronal Polarization Downstream of the Small GTPase Rab8a.
The acquisition of neuronal polarity is a complex molecular process that depends on changes in cytoskeletal dynamics and directed membrane traffic, regulated by the Rho and Rab families of small GTPases, respectively. However, during axon specification, a molecular link that couples these protein families has yet to be identified. In this paper, we describe a new positive feedback loop between Rab8a and Cdc42, coupled by Tuba, a Cdc42-specific guanine nucleotide-exchange factor (GEF), that ensures a single axon generation in rodent hippocampal neurons from embryos of either sex. Accordingly, Rab8a or Tuba gain-of-function generates neurons with supernumerary axons whereas Rab8a or Tuba loss-of-function abrogated axon specification, phenocopying the well-established effect of Cdc42 on neuronal polarity. Although Rab8 and Tuba do not interact physically, the activity of Rab8 is essential to generate a proximal to distal axonal gradient of Tuba in cultured neurons. Tuba-associated and Rab8a-associated polarity defects are also evidenced in vivo, since dominant negative (DN) Rab8a or Tuba knock-down impairs cortical neuronal migration in mice. Our results suggest that Tuba coordinates directed vesicular traffic and cytoskeleton dynamics during neuronal polarization.SIGNIFICANCE STATEMENT The morphologic, biochemical, and functional differences observed between axon and dendrites, require dramatic structural changes. The extension of an axon that is 1 µm in diameter and grows at rates of up to 500 µm/d, demands the confluence of two cellular processes: directed membrane traffic and fine-tuned cytoskeletal dynamics. In this study, we show that both processes are integrated in a positive feedback loop, mediated by the guanine nucleotide-exchange factor (GEF) Tuba. Tuba connects the activities of the Rab GTPase Rab8a and the Rho GTPase Cdc42, ensuring the generation of a single axon in cultured hippocampal neurons and controlling the migration of cortical neurons in the developing brain. Finally, we provide compelling evidence that Tuba is the GEF that mediates Cdc42 activation during the development of neuronal polarity.


Recent advances in NMR: expanding its role in rational drug design.
The technology of nuclear magnetic resonance spectroscopy continues to advance at a rapid pace. Recent improvements in gradient technology and the coupling of NMR to various chromatography methods will provide new opportunities in drug discovery. These opportunities include rapid high throughput screening to determine the receptor-bound conformations of small organic ligands. NMR coupled to liquid chromatography has opened a new door to the quantitative and qualitative analysis of complex mixtures including metabolites extracted from body fluids and extracts containing various natural products. This review will focus on the following four advances in NMR technology: 1) pulse-field gradient (PFG) NMR, 2) SAR (structure activity relationship) by NMR, 3) LC-NMR (liquid chromatography), and 4) application of membrane models for the study of neuropeptides. The information content available to medicinal chemists from each experiment will be discussed.


Description and morphometrical variability of a new species of Ligophorus and of Ligophorus chabaudi (Monogenea: Dactylogyridae) on Mugil cephalus (Teleostei) from the Mediterranean basin.
A comparative morphological study of specimens of Ligophorus spp. from Mugil cephalus in western Mediterranean and the Black Sea localities has been carried out, indicating the presence of 2 distinct forms, i.e., Ligophorus chabaudi and Ligophorus cephali n. sp. A detailed description of the latter and an up-to-date redescription of L. chabaudi are provided. The existence of these 2 morphological species was additionally supported by principal component analysis based on 19 metric characters of 87 specimens arranged in samples defined by parasite species and geographical locality. The analysis indicated consistent differences between species but not between localities; this pattern was well supported by jackknife procedures. Linear discriminant analyses showed that the main metric differences between the 2 species were attributable to the lengths of the dorsal and ventral bars and to the uncinulus length; use of the first 2 variables was enough to allocate all specimens studied to either form. The erection of L. cephali n. sp. raises the number of sympatric Mediterranean species of Ligophorus on M. cephalus to 3. The known geographical ranges of these species are compared.


Time-lapse cinemicrographic analysis of superficial cell behavior during and prior to gastrulation in Xenopus laevis.
Time-lapse cinemicrography was used to show what changes in the number, size, shape, arrangement and what movements of apices of superficial cells occur during epiboly, extension, convergence and blastopore formation in the blastula or gastrula of Xenopus laevis. Epiboly of the animal region occurs by apical expansion of superficial cells at a nearly constant rate from the midblastula to the midgastrula stage. Egression of deep cells into the superficial layer does not occur. Extension of the dorsal marginal zone begins in the late blastula stage with the rapid spreading of the apices of cells in this region and this continues until the onset of neurulation when rapid shrinkage begins. Extension and convergence of the dorsal marginal zone occurs by a rearrangement in which individual cells exchange neighbors and by a change in the shape of the cell apices. Regional differences in apical expansion are accompanied by differences in rate of anticlinal division of superficial cells such that cells in all sectors of the animal region and the marginal zone show similar patterns of decrease in apparent apical area. Shrinkage of the apices of bottle cells during blastopore formation is described. From this and other studies, a model of the cellular behavior of epiboly, extension and convergence is constructed and several hypotheses as to how these activities might generate the mechanical forces of the gastrulation movements are presented.


Down-regulation of interleukin-33 expression in oligodendrocyte precursor cells impairs oligodendrocyte lineage progression.
Interleukin-33 (IL-33), a member of the IL1 family, has been found to be expressed in oligodendrocytes (OLGs) and released as an alarmin from injured OLGs to work on other glial cell-types in the central nervous system. However, its functional role in OLGs remains unclear. Herein, we present that IL-33 was mainly expressed in the nucleus of CC1+ -oligodendrocytes (OLGs) in mouse and rat corpus callosum, as well as NG2+ -oligodendrocyte precursor cells (OPCs). The in vitro study indicated that the amount of IL-33 expressing in OPCs was higher when compared to that detected in OLGs. Results from the experiments using lentivirus-mediated shRNA delivery against IL-33 expression (IL33-KD) in OPCs showed that IL33-KD reduced the differentiation of OLGs into mature OLGs along with the down-regulation of OLG differentiation-related genes and mature OLG marker proteins, myelin basic protein (MBP) and proteolipid protein (PLP). Alternatively, we observed reduced differentiation of OLGs that were prepared from the brains of IL-33 gene knockout (IL33-KO) mice with anxiolytic-like behavior. Observations were correlated with the results showing lower levels of MBP and PLP in IL33-KO cultures than those detected in the control cultures prepared from wildtype (WT) mice. Transmission Electron Microscopy (TEM) analysis revealed that the myelin structures in the corpus callosum of the IL33-KO mice were impaired compared to those observed in the WT mice. Overall, this study provides important evidence that declined expression of IL-33 in OPCs suppresses the maturation of OLGs. Moreover, gene deficiency of IL-33 can disrupt OLG maturation and interfere with myelin compaction. Cover Image for this issue: doi: 10.1111/jnc.14522.


Structural basis for the autoinhibition of calcium/calmodulin-dependent protein kinase I.
The crystal structure of calcium/calmodulin-dependent protein kinase I has been determined in the autoinhibited form. The C-terminal regulatory region of the enzyme forms a helix-loop-helix segment that extends across the two domains of the catalytic core, making multiple inhibitory interactions. Elements of the first regulatory alpha helix and the loop interfere with the binding site for peptide substrates, while the loop and the second helix interact with the ATP-binding domain to induce conformational changes that obstruct the nucleotide binding pocket. One part of the calmodulin recognition element protrudes away from the catalytic domain and is potentially available for an initial interaction with calmodulin. The structure provides a view of an intact calmodulin target and suggests that substantial structural changes will accompany kinase activation by calmodulin binding to the regulatory region.


Computer simulation of a cytosolic calcium oscillator.
A new interpretation of existing data permits us to define a model capable of accounting for agonist-induced Ca2+ oscillations in the cytosol of electrically non-excitable cells. The model only requires one Ca2+ store, which contains Ca2+ channels controlled by inositol 1,4,5-trisphosphate and Ca2+. Computer simulations may generate different experimentally observed patterns of Ca2+ oscillations.


[Multiple nosocomial infections in a university hospital].
Multiple hospital-acquired infections (MHAI) have not been properly evaluated, and therefore data on their leading epidemiological features are lacking. In the present study, MHAI in a university hospital were evaluated during a 5 year period. Data were obtained from the institution program of hospital acquired infection surveillance, which is based on the daily review of microbiological reports with subsequent confirmation of the data in the service where the patient is admitted. The number of detected MHAI was 1,202 in 522 infected patients, corresponding to 10.3% of the overall number of patients with hospital-acquired infections (HAI). By age groups, the patients over 60 years were the most affected (62.7%), whereas the less affected were those below 40 years (13.6%). By hospital areas, the surgical area had the highest incidence (55.3%) and the gynecological area had the lowest incidence (2.4%). Double infections were the most common ones in all services, with 79.1% of the overall number. The service with the greatest number of patients with MHAI was Surgery (37.9%). Urinary tract infections were the most common type. The results show that male surgical patients over 60 years of age were the group at highest risk of MHAI.


Diagnostic role of circulating extracellular matrix-related proteins in non-small cell lung cancer.
Interactions between cancer cells and the surrounding microenvironment are crucial determinants of cancer progression. During this process, bi-directional communication among tumor cells and cancer associated fibroblasts (CAF) regulate extracellular matrix (ECM) deposition and remodeling. As a result of this dynamic process, soluble ECM proteins can be released into the bloodstream and may represent novel circulating biomarkers useful for cancer diagnosis. The aim of the present study was to measure the levels of three circulating ECM related proteins (COL11A1, COL10A1 and SPARC) in plasma samples of lung cancer patients and in healthy heavy-smokers controls and test whether such measurements have diagnostic or prognostic value. Gene expression profiling of lung fibroblasts isolated from paired normal and cancer tissue of NSCLC patients was performed by gene expression microarrays. The prioritization of the candidates for the study of circulating proteins in plasma was based on the most differentially expressed genes in cancer associated fibroblasts. Soluble ECM proteins were assessed by western blot in the conditioned medium of lung fibroblasts and by ELISA assays in plasma samples. Plasma samples from lung cancer patients and healthy heavy-smokers controls were tested for levels of COL11A1 and COL10A1 (n = 57 each) and SPARC (n = 90 each). Higher plasma levels of COL10A1 were detected in patients (p ≤ 0.001), a difference that was driven specifically by females (p < 0.001). No difference in COL11A1 levels between patients and controls was found. SPARC levels were also higher in plasma patients than controls (p < 0.001) with good performance in discriminating the two groups (AUC = 0.744). No significant association was observed between plasma proteins levels and clinicopathological features or survival. Soluble factors related to proficient tumor-stroma cross-talk are detectable in plasma of primary lung cancer patients and may represent a valuable complementary diagnostic tool to discriminate lung cancer patients from healthy heavy-smokers individuals as shown for the SPARC protein.


Factors associated with multimorbidity in England: an analysis of the English Longitudinal Study of Ageing.
Multimorbidity, defined as the presence of two or more long-term conditions, is a growing public health challenge, especially in terms of prevention and accumulation of long-term conditions among particular population cohorts. To date, efforts to understand multimorbidity has focused mainly on specific disease combinations, with little known about the sociodemographic factors associated with it. The study aimed to assess the factors associated with multimorbidity in England. A cross-sectional study was conducted using the English Longitudinal Study of Ageing (ELSA), a dataset of people aged 50 years and older. The study identified ten long-term conditions from waves 2 to 9. Wave 2 to 9 were conducted between June 2004 to July 2005, May 2006 to August 2007, May 2008 to July 2009, June 2010 to July 2011, May 2012 to June 2013, June 2014 to May 2015, May 2016 to June 2017 and June 2018 to July 2019, respectively. The study included people with two or more long-term conditions. We identified the number of long-term conditions and multimorbidity, and we examined their association with age, gender, ethnicity, marital status, employment status, education, weekly contact with relative, and feeling lonely, sad or depressed using multinomial logistic regression. Of 16 731 people recruited from wave 2 to wave 9, we identified 10 026 people with multimorbidity aged 50 years and older. The majority had two conditions (39%) and were female (55%), aged 50-69 years (32%), of white ethnicity (96%), married (69%) and unemployed (65·3%). The adjusted odds ratio (aOR) of having more than two long-term conditions increased with age, after adjusting for sex and ethnicity (≥5 conditions: aOR 12·89, 95% CI 2·23-3·76). Being female was associated with an increased risk of having more than two long-term conditions (≥5 conditions: aOR 1·21, 1·04-1·42). Similarly, being separated, divorced, or widowed were associated with having more than two long-term conditions (≥5 conditions: aOR 1·45, 1·21-1·74). Not owning a home was independently associated with more than two long-term conditions (≥5 conditions: aOR 1·59, 1·35-1·88). The current analysis used only ten long-term conditions that were available in the ELSA data, so a different association might have arisen if other conditions had been considered. Our findings provide insights into which particular groups of the multimorbid population could be the target of preventive public health strategies and wider clinical and social care interventions in England to reduce the burden of multimorbidity. National Institute for Health and Care Research (NIHR).


Dynamic Local Structure in Caesium Lead Iodide: Spatial Correlation and Transient Domains.
Metal halide perovskites are multifunctional semiconductors with tunable structures and properties. They are highly dynamic crystals with complex octahedral tilting patterns and strongly anharmonic atomic behavior. In the higher temperature, higher symmetry phases of these materials, several complex structural features are observed. The local structure can differ greatly from the average structure and there is evidence that dynamic 2D structures of correlated octahedral motion form. An understanding of the underlying complex atomistic dynamics is, however, still lacking. In this work, the local structure of the inorganic perovskite CsPbI3 is investigated using a new machine learning force field based on the atomic cluster expansion framework. Through analysis of the temporal and spatial correlation observed during large-scale simulations, it is revealed that the low frequency motion of octahedral tilts implies a double-well effective potential landscape, even well into the cubic phase. Moreover, dynamic local regions of lower symmetry are present within both higher symmetry phases. These regions are planar and the length and timescales of the motion are reported. Finally, the spatial arrangement of these features and their interactions are investigated and visualized, providing a comprehensive picture of local structure in the higher symmetry phases.


Sensitivity of MRI versus conventional screening in the diagnosis of BRCA-associated breast cancer in a national prospective series.
We wanted to compare the sensitivities of breast magnetic resonance imaging (MRI) and the conventional screening programme consisting of mammography (XRM) +/- ultrasound for early diagnosis of breast cancer in BRCA1/2 mutation carriers. BRCA1/2 mutation carriers were examined prospectively by both breast MRI and XRM +/- ultrasound. Eight hundred and sixty-seven MRI examinations were carried out in 445 BRCA1 and 46 BRCA2 mutation carriers. A total of 25 cancers were observed, five (20%) as interval cancers. At the time of diagnosis, sensitivity to detect cancer was 19/22=86% for MRI and 12/24=50% for XRM. Twenty-one were examined by both methods at the time of diagnosis. In the19 BRCA1 mutation carriers among them, MRI had a sensitivity of 1/3(33%) to diagnose DCIS and 15/16 (94%) among the invasive cancers. For XRM the sensitivities were 1/3(33%) for DCIS, 3/7(42%) for pT1b, 3/6(50%) for pT1c, and 3/3/100%) for pT2. In the two BRCA2 mutation carriers, both were demonstrated by breast MRI, neither was detected by XRM. Breast MRI had increased sensitivity compared to XRM to diagnose all cancers staged less than pT2.


To dope or not to dope: the effect of sonicating single-wall carbon nanotubes in common laboratory solvents on their electronic structure.
Single-wall carbon nanotubes (SWCNTs) are commonly dispersed via sonication in a solvent prior to functionalization. We show that solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and o-dichlorobenzene lead to an upward shift in the Raman response of the SWCNTs. We have used o-dichlorobenzene as a model molecule to explain this effect, and an upward shift of 9 cm(-1) is observed in the D* band. This blue shift is associated with p-type doping and is triggered only when the nanotubes are sonicated in the solvent. Sonication decomposes the chlorinated solvents, and new species (Cl2 and HCl(g)) are formed. The catalytic Fe nanoparticles inherently present in the nanotubes are etched by chlorine and hydrogen chloride to form iron chlorides during sonication in the solvent. The dopant was identified by X-ray photoelectron spectroscopy. With such knowledge of doping, the choice of solvent becomes crucial for any chemical reaction and can be intentionally tuned to produce SWCNTs films for electronics applications.


Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy.
CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (<36 months). Benefit (PFS hazard ratio, ORR increase) from abemaciclib was observed in all patient subgroups. Patients with indicators of poor prognosis had the largest benefit from the addition of abemaciclib. However, in MONARCH 3, for patients with certain good prognostic factors (TFI ≥ 36 months, bone-only disease) ET achieved a median PFS of >20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib.